Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM

OBJECTIVE: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. APPROACH AND RESULTS: Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. CONCLUSIONS: We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation

Molecular mechanisms of toxicity of silver nanoparticles in zebrafish embryos.

addresses: Biosciences, College of Life and Environmental Sciences, Geoffrey Pope Building, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK. [email protected]: Journal Article; Research Support, Non-U.S. Gov'tThis is an open access article that is freely available in ORE or from the publisher's web site. http://pubs.acs.org/doi/abs/10.1021/es401758d. Please cite the published version© 2013 American Chemical SocietySupporting Information: Further details on the methodology and results for the characterization of the silver particles used for the exposures, mortality curves, sequencing analysis, and a number of supporting figures and tables. This material is available free of charge via the Internet at http://pubs.acs.org.Silver nanoparticles cause toxicity in exposed organisms and are an environmental health concern. The mechanisms of silver nanoparticle toxicity, however, remain unclear. We examined the effects of exposure to silver in nano-, bulk-, and ionic forms on zebrafish embryos (Danio rerio) using a Next Generation Sequencing approach in an Illumina platform (High-Throughput SuperSAGE). Significant alterations in gene expression were found for all treatments and many of the gene pathways affected, most notably those associated with oxidative phosphorylation and protein synthesis, overlapped strongly between the three treatments indicating similar mechanisms of toxicity for the three forms of silver studied. Changes in oxidative phosphorylation indicated a down-regulation of this pathway at 24 h of exposure, but with a recovery at 48 h. This finding was consistent with a dose-dependent decrease in oxygen consumption at 24 h, but not at 48 h, following exposure to silver ions. Overall, our data provide support for the hypothesis that the toxicity caused by silver nanoparticles is principally associated with bioavailable silver ions in exposed zebrafish embryos. These findings are important in the evaluation of the risk that silver particles may pose to exposed vertebrate organisms.Natural Environment Research Council (NERC)NERC Biomolecular Analysis FacilityUK Environment AgencySystems Biology Seed fund, University of Exete

Methods to study microbial adhesion on abiotic surfaces

Microbial biofilms are a matrix of cells and exopolymeric substances attached to a wet and solid surface and are commonly associated to several problems, such as biofouling and corrosion in industries and infectious diseases in urinary catheters and prosthesis. However, these cells may have several benefits in distinct applications, such as wastewater treatment processes, microbial fuel cells for energy production and biosensors. As microbial adhesion is a key step on biofilm formation, it is very important to understand and characterize microbial adhesion to a surface. This study presents an overview of predictive and experimental methods used for the study of bacterial adhesion. Evaluation of surface physicochemical properties have a limited capacity in describing the complex adhesion process. Regarding the experimental methods, there is no standard method or platform available for the study of microbial adhesion and a wide variety of methods, such as colony forming units counting and microscopy techniques, can be applied for quantification and characterization of the adhesion process.This work was financially supported by: Project UID/EQU/00511/2013-LEPABE, by the FCT/MEC with national funds and co-funded by FEDER in the scope of the P2020 Partnership Agreement; Project NORTE-07-0124-FEDER-000025 - RL2_Environment&Health, by FEDER funds through Programa Operacional Factores de Competitividade-COMPETE, by the Programa Operacional do Norte (ON2) program and by national funds through FCT - Fundacao para a Ciencia e a Tecnologia; European Research Project SusClean (Contract number FP7-KBBE-2011-5, project number: 287514), Scholarships SFRH/BD/52624/2014, SFRH/BD/88799/2012 and SFRH/BD/103810/2014

Cell cycle profiling reveals protein oscillation, phosphorylation, and localization dynamics

The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics

Exploring sense of community within an online healthcare context

This paper argues that organisations considering corporate community involvement within online communities need to understanding how the notion of sense of community (SOC) is manifested and experienced within such stakeholder groups. This is based on the assumption that CCI is a form of corporate social responsibility that goes beyond the mere funding of charitable activities but involves a deeper involvement and participation within the life of the community (Moon and Muthuri 2006). Hence, it is expected that the corporation not only allocates significant amount of time and resources to such involvement (Yekini et al. 2017), but also implies a more in-depth understanding of the community itself. Therefore, this paper argues that in order for CSR managers to better identify and engage with relevant online communities, they need to be able to understand and apply the notion SOC within an online context. The case of an online healthcare community, hosted by a charitable institution in the UK, is presented to illustrate and support this argument

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects

Differences in Preferences Towards the Environment: The Impact of a Gender, Age and Parental Effect

The paper investigates empirically the differences in preferences towards protection of the environment. Using seven different dependent variables to focus on the impact of age, gender and children we use a large micro data set covering data from 33 Western and Eastern European countries. The results indicate that women have both a stronger preference towards the environment and a stronger willingness to contribute. Moreover, we observe the tendency of a negative correlation between age and environmental preferences. However, a positive effect is visible once we focus on the impact of age on social norms (environmental morale). Finally, we were not able to observe that having children is positively correlated with a stronger preference towards the environment

Bacterial Pili exploit integrin machinery to promote immune activation and efficient blood-brain barrier penetration

Group B Streptococcus (GBS) is the leading cause of meningitis in newborn infants. Bacterial cell surface appendages, known as pili, have been recently described in streptococcal pathogens, including GBS. The pilus tip adhesin, PilA, contributes to GBS adherence to blood-brain barrier (BBB) endothelium; however, the host receptor and the contribution of PilA in central nervous system (CNS) disease pathogenesis are unknown. Here we show that PilA binds collagen, which promotes GBS interaction with the α2β1 integrin resulting in activation of host chemokine expression and neutrophil recruitment during infection. Mice infected with the PilA-deficient mutant exhibit delayed mortality, a decrease in neutrophil infiltration and bacterial CNS dissemination. We find that PilA-mediated virulence is dependent on neutrophil influx as neutrophil depletion results in a decrease in BBB permeability and GBS–BBB penetration. Our results suggest that the bacterial pilus, specifically the PilA adhesin, has a dual role in immune activation and bacterial entry into the CNS

Public Goods, Signaling, and Norms of Conscientious Leadership

I study a sequential-move public goods game based on the notion that leadership comes with an obligation; conscientious leadership. Provision by the leader of an amount of the public good below a minimum imposes a psychological cost on the follower which increases his unit cost of contribution. The leader has private information about his type and his cost of contributing to the public good. The model combines a follower’s concern for fairness and informational signaling about conscientious leadership. I find that, under certain conditions, the follower’s equilibrium contribution is an increasing or non-monotonic function of the leader’s equilibrium contribution. The non-monotonicity result is consistent with evidence in a recent field experiment (Jack and Recalde, J. Public Econ, 2015) but cannot be obtained in previous theoretical models of voluntary public goods games that were based on only signaling information (i.e., about the quality of the public good or the return to contributions to the public good). Surprisingly, I find that, for this result to hold, the follower’s distaste for non-conscientious leadership must be sufficiently low. I also find that the leader may not act conscientiously if he does not have an informational advantage to exploit